This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To date, the most promising FDA approved clinical applications of [unreadable]9-Tetrahydrocannabinol (THC) are for the control of chemotherapy associated nausea and vomiting and for appetite stimulation for AIDS patients suffering from anorexia as a result of wasting syndrome. THC also demonstrates other biological activities which lend themselves to possible additional therapeutic applications. Currently, the only FDA approved dosage form is an oral, soft gelatin capsule, that is expensive, results in inconsistent pharmacokinetic profiles, allows the drug to undergo extensive first-pass metabolism and exhibits undesirable side effects. This project will test the hypothesis that selected [unreadable]9-THC pro-drugs incorporated into a hot-melt extruded "Transmucosal Matrix Patch" (TMP) delivery system will increase bioavailability of THC, following application to a subject's oral mucosa. Our approach in Aim 1 is to identify THC pro-drugs that are suitable for oral transmucosal delivery. Aim 2 will include the formulation and production of preliminary THC pro-drug incorporated TMP systems, including testing and evaluation of the preliminary systems (in vitro) to determine lead formulations. Aim 3 will involve the hot-melt extrusion, die-cutting and packaging of the lead systems, followed by bioadhesion, dissolution, permeability and stability testing to identify optimal TMP systems for each THC pro-drug. Optimized TMP formulations will be tested in an animal model in Aim 4 to determine pharmacokinetic profiles and confirm improved bioavailability. Incorporation of THC pro-drugs into a hot-melt extruded system as an alternate, more efficient method of delivery will have a tremendous impact on many chronically ill patients.